SAR of a series of inhaled A2A agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data

Mantell, Simon J.; Stephenson, Peter T.; Monaghan, Sandra M.; Maw, Graham N.; Trevethick, Michael A.; Yeadon, Michael; Walker, Don K.; Selby, Matthew D.; Batchelor, David V.; Rozze, Stuart; Chavaroche, Helene; Lemaitre, Arnaud; Wright, Kate; Whitlock, Lynsey; Stuart, Emilio F.; Wright, Patricia; Macintyre, Fiona

doi:10.1016/j.bmcl.2009.05.027

Cited by 25 publications

(23 citation statements)

References 12 publications

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“…It might be argued that such a low temperature cannot be representative for residence times observed in vivo . However, it was reported in a guinea pig bronchoconstriction model that UK432,097 (the agonist with the longest residence time in our studies) had a duration of action that lasted over 8 h, whereas the effect of the reference agonist CGS21680 quickly returned to baseline within 60 min (Mantell et al ., 2008; 2009). Admittedly, the long‐lasting effect is likely to be influenced by a number of other factors such as dissolution rate, system pharmacokinetics or tissue residence/rebinding (Vauquelin and van Liefde, 2006; Vauquelin and Charlton, 2010).…”

Section: Discussionmentioning

confidence: 51%

Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time

Guo

Mulder‐Krieger

IJzerman

et al. 2012

British J Pharmacology

163

173

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BACKGROUND AND PURPOSEThe adenosine A2A receptor belongs to the superfamily of GPCRs and is a promising therapeutic target. Traditionally, the discovery of novel agents for the A2A receptor has been guided by their affinity for the receptor. This parameter is determined under equilibrium conditions, largely ignoring the kinetic aspects of the ligand-receptor interaction. The aim of this study was to assess the binding kinetics of A2A receptor agonists and explore a possible relationship with their functional efficacy. EXPERIMENTAL APPROACHWe set up, validated and optimized a kinetic radioligand binding assay (a so-called competition association assay) at the A2A receptor from which the binding kinetics of unlabelled ligands were determined. Subsequently, functional efficacies of A2A receptor agonists were determined in two different assays: a novel label-free impedance-based assay and a more traditional cAMP determination. KEY RESULTSA simplified competition association assay yielded an accurate determination of the association and dissociation rates of unlabelled A2A receptor ligands at their receptor. A correlation was observed between the receptor residence time of A2A receptor agonists and their intrinsic efficacies in both functional assays. The affinity of A2A receptor agonists was not correlated to their functional efficacy. CONCLUSIONS AND IMPLICATIONSThis study indicates that the molecular basis of different agonist efficacies at the A2A receptor lies within their different residence times at this receptor. AbbreviationsADA, adenosine deaminase; BCA, bicinchoninic acid; CHAPS, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate; CI, cell index; HEK293hA2AR, human embryonic kidney 293 cells stably expressing the hA2A receptor; k3, the association rate constant of the unlabelled ligand; k4, the dissociation rate constant of the unlabelled ligand; RT, residence time; Z, cell-electrode impedance; ZM241385, 4-(2-[7-amino-2-(2-furyl) [1,2,4]

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Section: Discussionmentioning

confidence: 51%

Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time

Guo

Mulder‐Krieger

IJzerman

et al. 2012

British J Pharmacology

163

173

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“…However, adenosine insertions at certain positions of single‐stranded DNA can result in loss of the inhibitory effect. Adenosines can be anti‐inflammatory through the A(2A) receptor 71–74 . Synergistic interaction has been reported 75,76 between the A(2A) receptor and the receptors TLR2, TLR3, TLR4, TLR7 and TLR9, resulting in down‐regulation of tumour necrosis factor‐α release upon murine macrophage activation and human peripheral blood mononuclear cell stimulation.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

et al. 2012

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SummaryThe Toll-like receptors (TLRs) 3, 7, 8 and 9 stimulate innate immune responses upon recognizing pathogen-derived nucleic acids. TLR3 is located on the cell surface and in cellular endosomes and recognizes double-stranded viral RNA or the synthetic mimic poly rI:rC. Recently, unformulated small interfering RNA (siRNA) has been reported as ligand for surface-expressed murine TLR3. Blockage of TLR3 is achieved by singlestranded DNA. We confirm and expand the observation that poly rI:rCmediated TLR3 immune activation is blocked in a sequence-, length-, backbone-and CpG-dependent manner. However, human TLR3 is not activated by siRNA, which may be the result of differences in the amino acid composition of the TLR3 loop 1 of mice and humans. Although CD14 was previously described as a co-receptor for murine TLR3 and other nucleic acid-recognizing TLRs, human CD14 acts only as co-receptor to human TLR9, but not TLR3, TLR7 or TLR8. We show that CD14 up-regulates the TLR9 immune response of A, B and C-class oligodeoxynucleotides but down-regulates the phosphoro-diester version of B-class oligodeoxynucleotides.

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“…Recently, efforts have been undertaken to obtain A 2A agonists which show site-specific action. A 2A agonists, such as 18 have been developed for the treatment of bronchial inflammation (constructive pulmonary disease, COPD) by inhalation with limited systemic exposure [44]. In another approach 5′-phosphate prodrugs of A 2A agonists have been prepared (e.g.…”

Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

Recent developments in adenosine receptor ligands and their potential as novel drugs

Müller

Jacobson

2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

387

461

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Medicinal chemical approaches have been applied to all four of the adenosine receptor (AR) subtypes (A1, A2A, A2B, and A3) to create selective agonists and antagonists for each. The most recent class of selective AR ligands to be reported is the class of A2BAR agonists. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates. Prodrug approaches have been developed which improve the bioavailability of the drugs, reduce side-effects, and/or may lead to site-selective effects. The A2A agonist regadenoson (Lexiscan®), a diagnostic drug for myocardial perfusion imaging, is the first selective AR agonist to be approved. Other selective agonists and antagonists are or were undergoing clinical trials for a broad range of indications, including capadenoson and tecadenoson (A1 agonists) for atrial fibrillation, or paroxysmal supraventricular tachycardia, respectively, apadenoson and binodenoson (A2A agonists) for myocardial perfusion imaging, preladenant (A2A antagonist) for the treatment of Parkinson’s disease, and CF101 and CF102 (A3 agonists) for inflammatory diseases and cancer, respectively. This article is part of a Special Issue entitled: “Adenosine Receptors”.

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SAR of a series of inhaled A2A agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data

Cited by 25 publications

References 12 publications

Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time

Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

Recent developments in adenosine receptor ligands and their potential as novel drugs

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SAR of a series of inhaled A2A agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data

Cited by 25 publications

References 12 publications

Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time

Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

Recent developments in adenosine receptor ligands and their potential as novel drugs

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Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time

Functional efficacy of adenosine A_2A receptor agonists is positively correlated to their receptor residence time